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A Soluble Form of Lymphocyte Activation Gene-3 (IMP321) Induces Activation of a Large Range of Human Effector Cytotoxic Cells

Chrystelle Brignone^*, Caroline Grygar^*, Manon Marcu^*, Knut Schäkel and Frédéric Triebel^1,*

^* Immutep, Parc Club Orsay, Orsay, France; and Department of Dermatology and Institute of Immunology Medical, Faculty Carl Gustav Carus, Technische Universität, Dresden, Germany

The principal antitumor immune response is mediated through the activation of type 1 cytotoxic (Tc1) CD8 T cells, NK cells, and monocytes/macrophages. In this study, we investigated the potency of a clinical-grade soluble form of lymphocyte activation gene-3 protein (IMP321), a physiological high-affinity MHC class II binder, at inducing in PBMCs an appropriate cytotoxic-type response in short-term ex vivo assays. We found that IMP321 binds to a minority (<10%) of MHC class II ⁺ cells in PBMCs, including all myeloid dendritic cells, and a small fraction of monocytes. Four hours after addition of IMP321 to PBMCs, these myeloid cells produce TNF- and CCL4 as determined by intracellular staining. At 18 h, 1% of CD8⁺ T cells and 3.7% NK cells produce Tc1 cytokines such as IFN- and/or TNF- (mean values from 60 blood donors). Similar induction was observed in metastatic cancer patient PBMCs, but the values were lower for the NK cell subset. Early APC activation by IMP321 is needed for this Tc1-type activation because pure sorted CD8⁺ T cells could not be activated by IMP321. Only Ag-experienced, fully differentiated granzyme⁺ CD8 T cells (effector and effector memory but not naive or central memory T cells) are induced by IMP321 to full Tc1 activation. In contrast to IMP321, TLR1-9 agonists induce IL-10 and are therefore unable to induce this Tc1 IFN-⁺ response. Thus, IMP321 has many properties that confirm its potential to be a new class of immunopotentiator in cancer patients.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Frédéric Triebel, Immutep, Parc Club Orsay, 2 rue Jean Rostand, 91893 Orsay, France. E-mail address: ftriebel{at}immutep.com

² Abbreviations used in this paper: Tc1, type 1 cytotoxic T cell; DC, dendritic cell; LAG-3, lymphocyte activation gene-3; sLAG-3, serum protein LAG-3; hIgG1, human IgG1; CBA, cytometric bead array; CM, central memory; EM, effector memory; Treg, regulatory T cell.

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				C. Brignone, B. Escudier, C. Grygar, M. Marcu, and F. Triebel A Phase I Pharmacokinetic and Biological Correlative Study of IMP321, a Novel MHC Class II Agonist, in Patients with Advanced Renal Cell Carcinoma Clin. Cancer Res., October 1, 2009; 15(19): 6225 - 6231. [Abstract] [Full Text] [PDF]

				C. Casati, C. Camisaschi, L. Novellino, A. Mazzocchi, F. Triebel, L. Rivoltini, G. Parmiani, and C. Castelli Human Lymphocyte Activation Gene-3 Molecules Expressed by Activated T Cells Deliver Costimulation Signal for Dendritic Cell Activation J. Immunol., March 15, 2008; 180(6): 3782 - 3788. [Abstract] [Full Text] [PDF]